IL-17 is an essential component of the immune response to many pathogens and allergens. A common source of IL-17 is CD4+ T helper 17 (Th17) cells. These cells differentiate from nave CD4 cells into IL-17 producing cells at peripheral sites and are termed, conventional Th17 cells (cTh17). Recently, we and others discovered another population of IL-17 producing CD4+TCR+ T cells that differentiate into IL-17 secreting cells during their development in the thymus, prior to their migration into the periphery. These T cells are termed natural Th17 (nTh17) cells and are present in humans as well as mice. Recent findings reveal that nTh17 cells migrate to peripheral sites, including the lung, and further suggest these cells may be important in pathological conditions including asthma. Although nTh17 and cTh17 cells have similar cytokine profiles, our preliminary data suggest that nTh17 T cells are not simply CD4 T cells that are primed for IL-17 production in the thymus instead of the periphery, but are fundamentally distinct with specific roles in the immune system. Given the importance of IL-17 early in immune responses, we speculate that during selection, a subset of thymocytes is directed to make IL-17 to ensure the generation of a population capable of rapid IL-17 release. Until recently, it was not possible to distinguish the biologic role of nTh17 and cTh17 cells. However, we have discovered that nTh17 and cTh17 cells utilize different components of the Akt/mTOR/HIF signaling pathway for IL-17 production. Using carefully designed mice with defects in either nTh17 or cTh17 cell development we have the unique opportunity to determine the contribution of nTh17 versus cTh17 cells in airway disease. This proposal is focused on understanding how the molecular signals utilized by nTh17 cells during their development dictate their function following secondary TCR induced activation (Aim 1); and on exploiting the distinct developmental requirements of nTh17 and cTh17 T cells to establish whether they possess distinct roles in a well characterized mouse model of asthma ( Aim 2). In Aim 1 we will determine the role of HIF1 in nTh17 cells development and function using mice lacking the ability to signal through this pathway. In Aim 2, we will take advantage of our well-characterized model of Aspergillus fumigatus extract induced asthma to determine the contribution of nTh17 cells to asthma.